The use of hydrogels as delivery vehicles for drugs is well documented in U.S. Pat. No. 4,224,427. This patent sets out a detailed discussion of prior art relating to hydrogels and the formation of same.
The particular hydrogel invention disclosed in U.S. Pat. No. 4,224,427 relates to a process for preparing essentially uniform spherical beads of up to 5 mm diameter of a cross-linked, water insoluble hydrogel by suspension polymerization of a water-soluble monoolefin monomer and 0 to 70% of a water-insoluble monoolefinic monomer with a cross-linking agent and a polymerization initiator. The monoolefin monomers contain at least 5% by weight of a hydroxy substituted hydrophilic vinyl monomer. The water-soluble monoolefin monomer can be a hydroxyalkyl ester of acrylic and/or methacrylic acid, e.g., 2-hydroxyethyl, 2- or 3-hydroxypropyl, or 2,3-dihydroxypropyl esters, poly-ethoxylated hydroxyalkyl esters, N-vinyl-2-pyrrolidone or N-methyldiacrylamide. The water-insoluble monomer can be an alkyl acrylate or methacrylate, a vinyl ester of a carboxylic acid, a vinyl alkyl ester, acrylonitrile or styrene. The cross-linking agent is a polyolefinic macromer of molecular weight of 400 to 8000 such as a reaction product of a poly(tetramethylene oxide)glycol with a molecular weight of 600 to 4000, first terminated with toluene-2,4-diisocyanate or isophorone diisocyanate, and then endcapped with a hydroxyalkyl acrylate or methacrylate.
U.S. Pat. No. 4,423,099 to Mueller et al. dated Dec. 27, 1983 discloses hydrogel beads having an intepenetrating membrane incorporated therein. The preferred hydrogel beads are obtained by suspension polymerization of hydroxyalkyl (C.sub.2 -C.sub.4) acrylates or methacrylates, or N-vinyl pyrrolidone containing mixtures, for example, a copolymer of hydroxyethyl methacrylate and N-vinyl pyrrolidone cross-linked with a macromer, being a reaction product of isophorone diisocyanate capped with poly tetramethylene oxide. Other cross-linking agents disclosed are ethylene glycol diacrylate or methacrylate, di-ethylene glycol, polyethylene glycol-diacrylates or methacrylates, acrylate, neopentylglycol diacrylate, divinyl benzene, ethylene glycol divinyl ether, di-allyl maleate or fumerate. The hydrogel beads are modified by incorporating therein an interpenetrating membrane which is less permeable than the hydrogel and formed by a condensation polymer which is interwoven with the substrate hydrogel network. This is accomplished by imbibing the hydrogel with a reactant A, followed by immersion of the hydrogel containing such reactant in a medium containing a coreactant B. Examples of reactants are diisocyanate and water, polyhydric alcohols, poly-primary and poly-secondary amines, aromatic amines, diisocyanates, di-acid chlorides of aliphatic di-carboxylic acids, dialdehydes, anhydrides such as maleic-, succinic-, alkenyl-succinic, phthalic-and tetrahydrophthalic anhydrides. Rapidly occurring reactions disclosed include "dialdehydes+amines to give poly-Schiff bases; diketones or dialdehydes+dihydrazine derivatives to give polyhydrazones; and base of free-radical catalyzed addition of dithiols to olefinic, acrylic or maleic compounds, like ethylene glycol diacrylate or poly(propylene glycol maleate)." It appears that the reaction product obtained is then reacted with a diisocyanate to form the interpenetrating polymer network.
U.S. Pat. No. 4,056,496 to Mancini et al discloses hydrogels which may be used in drug delivery systems formed by the polymerization of a dihydroxyalkyl acrylate or methacrylate, an alkyl acrylate or methacrylate and a cross-linking agent which may be ethylene glycol dimethacrylate (EGDMA) or tetraethylene glycol dimethacrylate, and a minor amount of an epoxidized alkyl acrylate or methacrylate.
U.S. Pat. No. 4,136,250 to Mueller et al discloses a polysiloxane hydrogel formed by copolymerization of a monomer such as 2-hydroxyethyl methacrylate, and a monomer such as N-vinyl pyrrolidone and a siloxane macromer cross-linking agent.
U.S. Pat. No. 4,379,864 to Gallop et al discloses hydrogels formed by polymerization of a dihydroxyalkyl acrylate, a water-insoluble alkyl acrylate or methacrylate, one or more vinylic monomers and/or hydrophilic acrylates including vinyl pyrrolidone and 2-hydroxyethyl methacrylate, and a cross-linking agent which can be ethylene glycol dimethacrylate or triethylene glycol dimethacrylate.
"Preparation and Characterization of Therapeutic Hydrogels as Oral Dosage Forms", Gyselinck et al, Gent, Belg., Acta Pharmaceutica Technologica 29(1) 1983 discloses hydrogel particles based on 2-hydroxyethyl methacrylate (HEMA) cross-linked with glycol dimethacrylate (GDMA), tripropylene glycol diacrylate (TPGDA), tetraethylene glycol diacrylate (TEGDA), pentaerythritol triacrylate (PETA) and hexanedioldiacrylate (HDDA). The hydrogel particles are loaded with procainamide.
"Zero-Order Drug Release from Glassy Hydrogel Beads", Ping I. Lee, Ciba-Geigy, discloses hydrogel beads containing 70% of 2-hydroxyethyl methacrylate (HEMA) and 30% of a polymeric cross-linking agent which is derived from poly-n-butylene oxide (M.W.=2000) by capping with isophorone-diisocyanate followed by reaction with excess HEMA; the beads were synthesized by free-radical suspension polymerization. The hydrogel beads were loaded with oxprenolol, a .beta.-blocker.
"Modeling Drug Release from Swellable Systems", Korsmeyer et al, School of Chemical Engineering, Purdue University, discloses model systems formed of copolymers of 2-hydroxyethyl methacrylate (HEMA) and N-vinyl pyrrolidone (NVP) which were bulk-polymerized in polyethylene vials and then lathe cut into disks of desired thickness.
"Drug Release from Hydrogel Devices with Rate-Controlling Barriers", Kim et al., Dept of Pharmaceutics, U. of Utah, Journal of Membrane Science, 7(1980) 293-303 discloses progesterone-dispersed monolithic devices prepared from either polyhydroxyethyl methacrylate (HEMA) or a copolymer of HEMA and methoxyethoxyethyl methacrylate (MEEMA) which were soaked in an ethanol solution of ethylene glycol dimethacrylate (EGDMA) followed by exposure to UV light to create a cross-linked zone at the outer edge.
"Gradient-IPN-Modified Hydrogel Beads: Their Synthesis by Diffusion-Polycondensation and Function as Controlled Drug Delivery Agents", Mueller et al, Ciba-Geigy Corp., Journal of Applied Polymer Science, Vol. 27, 4043-4064 (1982) discloses interpenetrating polymer network (IPN) membranes and gradient-IPN polymers synthesized by immersing cross-linked, .alpha.-hydroxyethylmethacrylate copolymer beads which were swollen in polyol in solutions of diisocyanates. Mueller et al form a polyurethane within a preformed water-swellable copolymer matrix: cross-linked polymers based on 2-hydroxyethylmethacrylate and N-vinylpyrrolidone are swollen with a diol or triol and a polyurethane containing IPN is formed by reaction with 2,4,4(2,2,4)-trimethylhexane-1,6-diisocyanate (TMDI).